Advanced Pharmacokinetics Flashcards
Phase I metabolism
creates a chemical functional group on a drug
(eg many Cyt-p450 reactions)
Phase II metabolism
conugation of a water soluble molecule to a functional group on a drug
(makes drug more water soluble and/or inactive)
Most drugs distribute
rapidly; reach a distribution equilibrium, behave as if in a single compartment
Rate of drug elimination is proportional to
concentration in plasma (first-order kinetics)
Drugs given by rapid IV administration disribute and are eliminated by
rapidly; first-order kinetics (proportional to concentration in plasma)
In short-term IV infusion, drug is administered
at a constant rate
In short-term IV infusion, drug is distributed and eliminated
rapidly; first-order
How does drug concentration rise in rapid-IV?
rapidly, administered all at once
How does drug concentration increase in short-term IV?
- does not rise constantly
- as concentration increases, rate of elimination increases
- tf as it accumulates, it accumulates slower and slower because elimination is increasing
- concentration rises, then plateaus
What happens to drug concentration when short-term IV infusion is stopped?
eliminated exponentially (as if it had been a bolus/rapid-IV administration)
What is the difference in peak concentration between rapid and short-term IV?
peak is much higher in rapid bc administered all at once; short-term is infused gradually, tf peak concentration will never be as high as rapid IV
What feature of drug concentration differentiates short and long term IV infusion?
long term IV infusion reaches a steady state drug concentration; short term IV infusion does not
The steady-state concentration of drug in long term IV infusion is proportional to
- the infustion rate
- rate of infusion = rate of elimination
- tf easy to ‘dial up’ a particular concentration in a patient by changing the rate of infusion:
- infusion rate = Css
- 2x infusion rate = 2x Css
- 0.5x infusion rate = 0.5x Css
How are multiple dosing and long term IV administrations related?
pattern of accumulation in long term IV infusion is the same if the drug is given at a constant rate or in a series of multpile doses; both are a constant rate
The dosing interval of most drugs is
half-life
What is a loading dose?
volume distribution x concentration
use to establish a steady-state blood concentration before administering multiple doses of a drug (usually with a long half-life)
Absorption of orally administered drugs is primarily
lipid diffusion in the small intestine
Absorption of orally administered drugs depends on
concentration in the small intestine (greater concentration = greater drive for absorption)
Elimiantion rate of orally administered drugs depends on
concentration in the blood (first order elimination)
What are the features of oral administration?
- peak concentration is not as high as IV
- some drug is eliminated during absorption
- not all drug may be absorbed from GI (absorption is not a factor in IV)
- some may be first-pass metabolised in the liver, reducing concentration in the blood
What is bioavailability?
- proportion of active drug that enters the systemic circulation
- (100% with IV, less via other routes)
- affected by:
- how much is absorbed
- how much of the drug undergoes:
- first pass hepatic metabolism (oral admin)
- local metabolism (eg in GI prior to absorption, at skin or muscle for intramuscular injection)
Bioavailability is calculated by
- area under the concetrantio vs time curves for IV and oral administration:
- (AUC-oral/AUC-IV) X 100%
- if oral bioavalability is less than IV, need to administer more drug to get the same dose:
- IV = 100mg; oral = 75%
- 100/0.75 = 133mg oral dose
What are the factors that complicate drug use?
- unusual drug behaviour
- interpatient variability
What are unusual drug behaviours?
- low bioavailability - drug is sensitive to variability
- slow distribution such that some is eliminated during distribution
- sufficiently high concentrations of drug to saturate elimination processes, making elimination rate constant (zero-order kinetics)
How does low bioavailability increase sensitivity to variability in concentration?
- 90+/-5%, variation is (95-85)/85 = 12%
- 10+/-5%, variation is (15-5)/5 = 200% –> pt ends up with twice as much drug as another
Drugs with low bioavailability need to be administered by
Routes that avoid first-pass metbolism:
- skin (patches)
- lungs (gas)
- nose
- rectum
- subcutaneous injection
these may have absorption factors that contribute to bioavailability; IV avoids both issues but not always appropriate
What are the consequences of rapid IV administration of a slow-distributing drug?
- rapidly distrubutes in central compartment (blood, heart, brain, liver, tissues)
- slowly distributes into peripheral compartment (fat and muscle)
-
both compartments comprise the volume distribution
- tf initially have a high concentration in a lower volume
- drug is eliminated from central while it distributes to peripheral
- reaches EQB
- after EQB, only elimination
What is the danger of slow-distributing drugs?
- peak concentration is higher than predicted by volume distribution
- takes longer to reach the peripheral comparments and therefore is concentrated in the central compartment
- if the drug has a narrow therapeutic index, this concentration can easily be in the toxic range
What is the consequence of zero order elimination (enzymes are saturated)?
- in single dosing, get constant elimination while the system is saturated and exponential elimination when concentration falls
- in multpile dosing, zero order elimination prohibits reaching a steady state
- increasing concentration doesn’t increase elimination
- tf concentration of drug continues to rise
- in practice, other enzyme systems take over = pseudo SS
What causes interpatient variability?
- age
- genetic factors
- idiosyncratic reactions
- disease
- drug-drug interactions
How does age affect drug concentration?
reduced excretion and metabolism at extremes of age increases the half-life and persistence of some drugs - tf may need lower doses if multi-dosing
Babies are deficient in
drug metabolizing enzymes, particularly phase II conjugation
tf increased plasma half life of drugs
Elderly are deficient in
Cyt-p450 enzymes
increases half-life of drugs
What genetic factors contribute to drug metabolism?
- polymorphisms of enzymes (fast or slow)
- ethnic expression eg ALDH in Chinese
In a pharmacodynamic drug-drug interaction
drug A modifies the effect of drug B without affecting its concentration
In a pharmacokinetc drug-drug interaction
drug A modifies the concentration of drug B at its receptor
To be clinically significant, drug-drug interactions require
- the drug affected to have a narrow tehrapeutic index
- its concentration-response curve is steep such that small changes in concentration have large changes in effect
Pharmacodynamic interactions can occur at
receptors eg antagonism; can cause physiological effects
Pharmacokinetic interactions act at the level of
- absorption
- distribution
- metabolism
- excretion
Pharmacokinetic interactions at the level of absorption
- alter gastric emptying rates
- decreased by opiates
- increased my metaclopramide
- formation of poorly-absorbed complexes
- calcium & tetracyclines
Pharmacokinetic interactions at the level of distribution
- displacement from plasma protein binding sites transiently increases [unbound drug]
- causes an increase in elimination that corrects [unbound drug]
- overall decrease in drug, but no change in ‘free drug’ in plasma
- eg aspirin displacing phenytoin
Pharmacokinetic interactions at the level of metabolism
- induction of p450 (rifampicin, ethanol) decreases half-life/concentration in plasma, and
- eg warfarin
- leads to increased bioactivation that can increase toxicity
- eg paracetamol
- inhibition of p450 (steroids, cimetidine) increases half-life/increases plasma concentration
- eg phenytoin, digoxin
Pharmacokinetic interactions at the level of excretion
- alter protein binding, affecting filtration
- alter tubular secretion (eg blocking it with probenic acid for masking)
- alter urine flow and pH (eg using bicarb to alkalize urine to tx aspirin overdose)
